Cancer cells excessively express tumor-associated antigens. The host immune system is considered to respond to the tumor-associated antigens and exert cellular immunity to eliminate the tumor. However, there exist various types of immune escape mechanisms in the tumor micro-environment or throughout the body, and when the host fails to eliminate the tumor, the tumor grows.
Recently it has been reported that indoleamine 2,3-dioxygenase (IDO), which is a tryptophan-metabolizing enzyme, inhibits the proliferation of T cells and NK cells and activates regulatory T cells, thereby causing the depression of the host immune system. The expression of IDO is increased in tumor tissues and induced by IFN-γ stimulation in cancer cells and dendritic cells (for example, J. Clin. Invest., vol. 117, No. 5, pp. 1147-1154 (2007)). In a human body, 90% of tryptophan, which is the essential amino acid, is metabolized into kynurenine and subsequently into 3OH-kynurenine, quinolinic acid, and the like in the kynurenine pathway, whose initiation step involves IDO. Activation of IDO decreases the tryptophan concentration and increases the kynurenine concentration in a local or systemic manner, and the tryptophan metabolites including kynurenine induce the death of T cells and NK cells (for example, J. Exp. Med., vol. 196, No. 4, pp. 447-457 (2002)). The tryptophan metabolism also induces the conversion of CD4+CD25− T cells into regulatory T cells (for example, Blood, vol. 109, No. 7, pp. 2871-2877 (2007)). In the culture supernatant of dendritic cells in which the expression of IDO is induced by INF-γ, the tryptophan concentration is decreased and the kynurenine concentration is increased. When T cells are co-cultured with such dendritic cells, T cell proliferation is suppressed compared to co-culture with unstimulated dendritic cells (for example, J. Exp. Med., vol. 196, No. 4, pp. 447-457 (2002)).
As described above, in the tumor environment with an increased expression of IDO, an increased kynurenine concentration induced by tryptophan metabolism suppresses antitumor effector cells, which is considered to be one of the immune escape mechanisms in tumors (for example, J. Clin. Invest., vol. 117, No. 5, pp. 1147-1154 (2007)).
An increased expression of IDO in the tumor tissues of colorectal cancer and prostate cancer has been reported (for example, Clin. Cancer Res., vol. 12, No. 4, pp. 1144-1151 (2006); and Eur. J. Cancer, vol. 44, No. 15, pp. 2266-2275 (2008)). In acute myeloid leukemia cells, IDO is constantly expressed (for example, Leukemia, vol. 21, pp. 353-355 (2007)). It has also been reported that when patients with endometrial cancer, melanoma or ovarian cancer has an increased expression of IDO, the patients will have a poor prognosis (for example, Br. J. Cancer, vol. 95, No. 11, pp. 1555-1561 (2006); J. Clin. Invest., vol. 114, No. 2, pp. 280-290 (2004); and Clin. Cancer Res., vol. 11, No. 16, pp. 6030-6039 (2005)). In adult T cell leukemia lymphoma and acute myeloid leukemia, the kynurenine/tryptophan ratio in the blood is increased (for example, Leuk. Res., vol. 33, No. 1, pp. 39-45 (2009); and Leuk. Res., vol. 33, No. 3, pp. 490-494 (2009)). It has also been reported that melanoma patients with an increased kynurenine/tryptophan ratio in the blood will have a poor prognosis (for example, Dermatology, vol. 214, No. 1, pp. 8-14 (2007)). As described above, IDO and/or kynurenine is considered to be involved in various types of solid cancers and hematologic cancers.
1-methyltryptophan (1-MT), which is a tryptophan derivative, antagonizes tryptophan, thereby inhibiting the production of kynurenine (for example, Cancer Res., vol. 67, No. 2, pp. 702-300 (2007)). 1-MT cancels the suppression of T cell proliferation in the presence of IDO-expressing cancer cells or IDO-expressing dendritic cells (for example, Cancer Res., vol. 67, No. 2, pp. 792-800 (2007)). Further, 1-MT induces major histocompatibility complex (MHC)-restricted rejection in allogeneic pregnant mice (for example, Nat. Immunol., vol. 2, No. 1, pp. 64-68 (2001)). These results suggest that inhibition of IDO suppresses the production of kynurenine and induces immunity.
1-MT shows an antitumor effect in tumor-bearing mice with mouse melanoma cells. This effect disappears in immunodeficient mice (for example, Cancer Res., vol. 67, No. 2, pp. 792-800 (2007)). These results suggest that the antitumor effect of 1-MT is based on immunostimulation by IDO inhibition-mediated inhibitory effect on the production of kynurenine.
In addition, compounds showing an inhibitory effect on the production of kynurenine and/or on IDO are known to exhibit an immunostimulatory effect (for example, Nat. Immunol., vol. 2, pp. 64-68 (2001)).
On the other hand, it has been reported that the IDO expression in PBMC correlates with the viral load in HIV positive patients (for example, Blood, vol. 109, pp. 3351-3359 (2007)). It has also been reported that chronic hepatitis C patients have an increased IDO mRNA level in the liver and an increased serum kynurenine/tryptophan ratio (for example, J Virol., vol. 81, No. 7, pp. 3662-3666 (2007)).
Further, compounds showing an inhibitory effect on the production of kynurenine and/or on IDO are known to be useful as an antitumor agent, an anti-AIDS agent, an anti-AIDS dementia agent, an anti-Alzheimer's disease agent, an antidepressant, or the like (for example, J Clin Invest., vol. 117, pp. 1147-1154 (2007); J Virol., vol. 81, pp. 11593-11603 (2007); Neuropathol Appl Neurobiol., vol. 31, pp. 395-404 (2005); Neurosci Lett., vol. 187, pp. 9-12 (1995); and Neuropsychopharmacology, vol. 33, pp. 2341-2351 (2008)).
As described above, IDO inhibitors and/or kynurenine production inhibitors are considered to foe promising preventive or therapeutic agents for diseases associated with the production of kynurenine, such as cancers, AIDS, AIDS dementia, Alzheimer's disease, depression, infections, and immune diseases.
On the other hand, pyrazine derivatives having an antagonistic effect on endothelin are known (see Patent Literature 1 and Non Patent literature 1).
Compounds known as a therapeutic agent for diseases in which chemokines are involved are
N-pyrazinyl-2-thiophenesulfonamide derivatives (see Patent Literature 2), N-pyrazinylbenzenesulfonamide derivatives (see Patent Literature 3), N-(2-quinoxalinyl)benzenesulfonamide derivatives (see Patent Literature 4), and the like. Compounds known as a chemokine receptor antagonist areN-pyrazinylbenzenesulfonamide derivatives,N-(2-quinoxalinyl)benzenesulfonamide derivatives (see Patent Literature 5 and 6),pyridopyrazin-2-on-3-ylmethanesulfonamide derivatives (see Patent Literature 7), and the like. Compounds known as a functional modulator of thymus and activation-regulated chemokine (TARC; CC cherookine ligand 17 (CCL17)) and/or of macrophage-derived chemokine (MDC: CC chemokine ligand 22 (CCL22)) are N-pyrazinylbenzenesulfonamide derivatives, N-(2-pyridopyrazinyl)benzenesulfonamide derivatives (see Patent Literature 8), and the like.
N-(2-quinoxalinyl)benzenesulfonamide derivatives having an inhibitory activity on phosphatidylinositol-3-kinase (PI3K) (see Patent Literatures 9 and 10), and the like, are known.
Also, a nitrogen-containing heterocyclic compound having an inhibitory effect on the production of kynurenine (see Patent Literature 11) is known.
Further, 2,3-disubstituted quinoxaline derivatives having GLP-1 agonist activity (see Patent Literature 12) are known.